Urolithiasis can have numerous predisposing etiologic factors. Some of the specific mechanistic steps in the formation of kidney stones have not been determined. Once the concentration of ions and/or macromolecules has reached supersaturation, a state of crystalluria exists within the urinary tract, and the formation of stones can occur through a multifaceted process. These steps include retention of the microcrystallites by the epithelial membranes, and growth by aggregation, matrix adhesion, epitaxial interactions, and/or agglomeration. This research proposal has three major Specific Aims: I) To study the retention of microcrystals by investigating the processes of crystal formation on and crystal binding to rat renal medullary/papillary (RMP) cells in primary culture. II) To study the possible role of epitaxial interactions between crystal structures observed in renal stones. III) To study the role of matrix and the degree of crystallinity on the mechanism of reorganization and maturation of renal stones. In Specific Aim I, we will question if RMP apical cell surfaces can serve as nucleation sites for kidney stone crystal nucleation? Do preformed renal stone crystals bind to the apical surface of RMP cells in primary culture? Are these crystal-membrane interactions influenced by inhibitors, and do the crystals damage RMP cells and their membranes? In Specific Aim II, we will study possible epitaxial interactions between renal stone crystals using our program EPITAX, and will model these interactions in real-time and in three-dimensions using sophisticated computer graphics. In Specific Aim III, we will utilize human kidney stones received by the National VA Crystal Identification Center to study the mechanism of stone maturation. We will determine if stones mature by a two-stage crystallization process where matrix is extruded during recrystallization and maturity. Also, the degree of crystallinity will be correlated with the type of crystal formed and matrix content and composition.